Preparation of isoquinolines



United States Patent 3,435,040 PREPARATIO 0F ISOQUlNOLINES Goetz E.Hardtmann, Madison, and Hans Ott, Convent Station, N. assignors toSandoz Inc., Hanover, NJ. No Drawing. Filed June 28, 1965, Ser. No.467,713 Int. Cl. C07d 35/20, 35/36, 57/02 US. Cl. 260-288 4 ClaimsABSTRACT OF THE DISCLOSURE This invention is directed to a process forthe preparation of hexahydroisoquinolobenzodiazepinones, particularlypharmaceutically acceptable compounds of the formula is. R

wherein R is either a chlorine atom (-Cl); a fluorine atom (-F);trifluoromethyl (--CF or nitro (NO R is either a hydrogen atom (-H);stratight chain (preferably lower) alkyl, e.g. methyl, ethyl, propyl andbutyl; or benzyl; and

each of R and R is either a hydrogen atom (-H); lower alkyl, e.g.methyl, ethyl, propyl, isopropyl and butyl; lower alkoxy, e.g. methoxy,ethoxy, propoxy, isopropoxy and butoxy; or, taken together,methylenedioxy (OCH O);

and to individual steps in the process. The overall process comprisesfive steps:

(A) GEN R m- X 4 N R R 1 R l II III IV N R; IV Il -NH I V VI q R NH VI YNH L. R1

VII

R 0 R4 N--CH2 -OR H VII Z-CH2-CO-R NH {,1 R1

VIII IX (E) IX +CH3O-CH2CH2-ON3 I wherein propyl and butyl; atom (--Cl)or a Pharmaceutically acceptable compounds I are useful as anti-anxietyagents. They are administered either orally or parenterally in standarddosage forms, e.g. tablets and capsules, in doses which vary fromcompound to compound and with the severity of the condition beingtreated.

Compounds II, III, V and VIII are either known compounds or are preparedby standard procedures from available compounds. Step A is effect-edunder reflux for from 2 to 6 hours with the reactants in contact. witheither stannic chloride (SnCl or titanium tetrachloride (TiCl A molarexcess of II is employed. Per part by weight of compound II, from about0.5 to about 1.5 parts by weight (depending upon the molecular weightratio) of III and from about 0.7 to about 5 parts by volume of thetetrachloride are employed.

Step B is preferably effected in from 2 to 12 hours at a temperaturefrom 50 to 60 C. with the reactants IV and V in contact with copperpowder (Cu) and cuprous chloride (CuCl or Cu cl Both the temperaturerange and the copper catalyst are essential to obtain particularly goodresults. Below 50 C. the reaction is unduly slow, and above 60 C.unwanted side-products result. The combination catalyst (Cu plus CuCl)results in good yields. Per part by weight of Compound IV, it ispreferred to use from 8 to 20 parts by weight of V, from 0.02 to 0.1part by weight of Cu and from 0.02 to 0.1 part by weight of CuCl.

Step C is effected under reflux for from 1 to 5 hours in a 3 solventwith sodium borohydride. Per part by weight of VI, from 0.1 to 0.5 partby weight of sodium borohydride and from to parts by volume of solventare employed. The preferred solvent is ethanol containing up to 20% ofwater, but this may be replaced by methanol, by propanol, by isopropanolor by diglyme. If diglyme is employed, the temperature is maintainedbetween 60 and 90 (1., rather than at reflux.

Step D is also effected under reflux and in a solvent. Atri(lower)alkylamine, e.g. trimethylamine, triethylamine,tripropylamine, ethyldimethylamine and tributylamine, is incorporated inthe reaction mixture prior to refluxing. The solvent is, preferably,ethanol, but may also be methanol, propanol or acetone. Refluxing iscontinued for from 3 to 10 hours within the temperature range of from 55 to 90 C. The molar ratio of VII:VIII:trialkylamine is usually Withinthe range of from l:(1.1 to 2) (1.1 to 2). From 10 to 50 parts by volumeof solvent are employed per part by Weight of VII.

For step E compound IX is refluxed in a solvent with sodiummethoxyethoxide for from 1 to 6 hours. Although the preferred solvent isfi-methoxyethanol, suitable other solvents, such as t.-butanol andisoamyl alcohol, may be used in lieu thereof. The refluxing temperatureis usually from 100 to 130 C. Per part by weight of IX, from 0.005 to0.1 part by weight of sodium methoxyethoxide and from 5 to 50 parts byvolume of solvent are employed.

Alternatively, step E (ring closure) is effected by refluxing IX inglacial acetic acid.

In the preceding steps A to E no variation of substituents within thescope of those indicated will preclude the running of any of thereactions under the contemplated conditions.

The following examples illustrate the invention, all temperatures beingin degrees centigrade, parts and percentages being in parts by weightunless otherwise specified, and the relationship between parts by weightand parts by volume being the same as that between the kilogram and theliter.

EXAMPLE 1 1-(2-chloro-5-trifluoromethyl-phenyl)-3,4-dihydroisoquinolinehydrochloride Reflux for 5 hours in 8 parts by volume of stannicchloride a solution of 10 parts of phenylethylchloride and 13 parts of2-chloro-5-trifluorornethylbenzonitrile. Add with intense cooling (DryIce/ acetone) to the cooled mixture sodium hydroxide solution until themixture is alkaline. Extract the very cloudy solution three times withethylacetate. Filter the organic phase; wash same with Water andsaturated sodium chloride solution; dry over sodium sulfate andevaporate in vacuo. Dissolve the residue in methylene chloride andsaturate with dry hydrogen chloride gas. Addition thereto ofdiethylether and cooling to 0 yields 7.5 parts of crystalline titlecompound, melting point (M.P.) 212 to 214 C. The compound may bepurified by sublimation at 100 to 0.5 mm. pressure.

Replacing the phenethylchloride with an equivalent of eitherm-(fi-chloroethyl)toluene, p-ethoxyphenethylchloride orl-(fi-chloroethyl)-3,4-methylenedioxybenzene results in the preparation,in similar manner, of the hydrochloride of the corresponding compoundIV.

Replacing the 2-chloro-5-trifluoromethylbenzonitrile with an equivalentof either 2,5-dichlorobenzonitrile, 2- bromo-S-nitrobenzonitrile or2-chloro-5-fluorobenzonitrile results in the preparation, in similarmanner, of the -hydrochloride of the corresponding compound 1V.

t EXAMPLE 2 l-t2-methylamino-S-trifluoromethyl-phenyl)-3,4-dihydroisoquinoline Heat to55 to 60 (autoclave) in 500 parts by volume of liquid methylamine amixture of 35 parts of 1-(2-chloro- S-trifiuoromethylphenyl)-3,4dihydroisoquinoline hydrochloride, 1.7 parts of cuprous chloride and 1.7parts of copper powder; maintain the resultant at 55 to 60 for 12 hours.Cool the resultant and evaporate the methylamine at room temperature.Treat the thus-obtained residue with 500 parts by volume of methylenechloride; filter oil insoluble material. Wash the organic phase twicewith water; dry over sodium sulfate and evaporate in vacuo to obtain 32parts of light yellow oil.

Replacing the methylamine with an equivalent of either ethylamine orbenzylamine results in the preparation, in similar manner, of thecorresponding compound VI. To obtain compounds VI wherein R is ahydrogen atom, liquid ammonia is employed under the same conditions.

Replacing the title compound of Example 1 with either1-(2-bromo-S-trifluoromethyl-phenyl)-6-methoxy-3,4 dihydroisoquinolinehydrochloride, 1-(2,5-dichlorophenyl)- 7-methyl-3,4-dihydroisoquinolinehydrochloride or either of the corresponding free bases, results in thepreparation, in similar manner, of the corresponding compound VI.

EXAMPLE 3 1-(2-methylamino-5-trifluoromethyl-phenyl)-1,2,3,4-tetrahydroisoquinoline Ha F 0 Reflux for two hours in 400 parts byvolume of ethanol a mixture of 30 parts ofI-(Z-methylamino-S-trifluoromethyl-phenyl)-3,4-dihydroisoquinoline and 8parts of sodium borohydride. Cool the obtained solution and treat samewith 2 N hydrochloric acid to destroy excess sodium borohydride.Alkalize the resultant with 2 N sodium hydroxide solution and distilloff the solvent in vacuo until parts by volume remain. Extract theresultant mixture three times with ethylacetate. Wash the organic phasetwice with saturated sodium chloride solution; dry same over sodiumsulfate and evaporate in vacuo to obtain 12 parts of title compound,M.P. to 129, crystallized from ethanol.

EXAMPLE 4 1- (2-rnethylamino-5-trifluoromethyl-phenyl)-2-carbethoxymethyl-1,2,3,4-tetrahydroisoquinoline 1 i CH3 FaC Refluxfor five hours in 30 parts by volume of ethanol a mixture of 1 part of1-(Z-methylamino-S-trifluoromethyl-phenyl)-1,2,3,4-tetrahydroisoquinoline,1 part of ethylbromoacetate and 0.7 part of triethylamine. Evaporate thesolvent in vacuo; dissolve the residue in methylene chloride; wash thesolution with water; dry same over sodium sulfate and evaporate invacuo. Distill the oily residue at 130 and 0.5 mm. pressure andcrystallize the distillate from pentane to obtain 1.1 parts of titlecompound, M.P. 80 to 82.

EXAMPLE 5 chloride HCl Add to a solution of 0.1 part of metallic sodiumin 200 parts by volume of absolute Z-methoxy-ethanol 10 parts of1-(2-methylamino-5-trifiuoromethylphenyl)-2-carbethoxymethyl-1,2,3,4-tetrahydroisoquinoline and reflux for one hour.Distill the solvent off in vacuo and dis solve the residue in methylenechloride. Wash the organic phase twice with water; dry oven sodiumsulfate and evaporate in vacuo to obtain 9.5 parts of a light brown oil.Dissolve the oil in ethylacetate and saturate the solution with dryhydrogen chloride gas. The hydrochloride precipitates on cooling andmelts at 221 to 225.

The invention and its advantages are readily understood from theforegoing description. Although the several steps have been correlatedto produce a specific type of end-product, various changes can be madein the nature and arrangement of the steps and in the starting materialsand intermediates to which they are applied without departing from thespirit and scope of the invention or sacrificing its materialadvantages. Exemplifica- .tions set forth herein are merely illustrativeembodiments.

What is claimed is:

1. A process for preparing a 1-(ortho-X)-phenyl-3,4- dihydroisoquinolinewhich comprises refluxing for from 2 to 6 hours a mixture of ano-halobenzonitrile of the formula GEN the group consisting a fluorineatom, trifluoro- 6 wherein each of R and R is a member selected from thegroup consisting of a hydrogen atom, straight chain alkyl having from 1to 4 carbon atoms and straight chain alkoxy having from 1 to 4 carbonatoms and, taken together, methylenedioxy; and from about 0.7 to about 5parts by volume of a member selected from the group consisting ofstannic chloride and titanium tetrachloride per part by weight of thefl-phenethylchloride, the relationship of parts by weight to parts byvolume being the same as that between the kilogram and the liter.

2. A process for preparing a 1-(o-amino)phenyl-3,4- dihydroisoquinolinewhich comprises maintaining at a temperature within the range of from 50to 60 C. a compound of the formula the group consista fluorine atom,triwherein R is a member selected from the group consisting of ahydrogen atom, straight chain lower alkyl 'and benzyl; and in contactwith a catalyst comprising cuprous chloride and copper powder.

3. A process according to claim 1 wherein R is trifluoromethylene, X isa chlorine atom and R and R are both hydrogen atoms.

4. A process according to claim 2 wherein R is trifluoromethyl, R ismethyl, X is a chlorine atom, and R and R are both hydrogen atoms.

References Cited UNITED STATES PATENTS 2,634,292 4/1953 Hellerback260-286 X 2,778,833 1/1957 Surrey 260286 3,205,233 9/1965 Clarkson260-288 ALEX MAZEL, Primary Examiner. D. G. DAUS, Assistant Examiner.

US. Cl. X.R. 260-289, 239.3, 465, 287, 651, 999

